Our research has identified that exposure of the surface of the eye to a dry or high osmolarity environment initiates a 2 phase response. The first phase of this response is increased expression of a variety of stress response genes by the epithelial cells on the surface of the eye, including inflammatory mediators and factors that promote abnormal "skin like" differentiation and premature cell death. Our data suggests that dry eye induced changes in gene expression are due in part to activation of mitogen activated protein kinase (MARK) signaling pathways in the ocular surface epithelia, particularly the c-jun n-terminal kinase (JNK) pathway. The second phase of the ocular surface response is recruitment of inflammatory/immune cells from the blood to the surface of the eye. Among these cells are type 1 T helper lymphocytes (Th1) that produce interferon gamma, a cytokine that has been shown to alter mucosal epithelial differentiation and to decrease the number of mucus producing goblet cells in non-ocular mucosal tissues. Based on our preliminary findings, we hypothesize that each of these phases plays a key role in the pathogenesis of keratoconjunctivitis sicca (KCS), the sight-threatening ocular surface epithelial disease of dry eye. Three proposed Specific Aims will test this hypothesis. Aim 1 will confirm that dry eye and osmotic stress promote prduction of cornified envelope (CE) differentiation proteins and their cross-linking transglutaminases by the ocular surface epithelium, a process that results in an irregular poorly wettable surface that is a hallmark of keratoconjunctivitis sicca. It will investigate the role of MARK signaling pathways in the abnormal production of these cornified envelope precursors. Specific Aim 2 will investigate the mechanism by which CD4+ T cells are recruited to the conjunctiva (Phase 2) in dry eye and will characterize the type and cytokine profile of these cells. Specific Aim 3 investigates the hypothesis that cytokines produced by type 1 and type 2 helper T lymphocytes differentially modulate conjunctival goblet cell differentiation and production of differentiation associated factors by the ocular surface epithelia. These studies are likely to uncover key mediators in the pathogenesis of keratoconjunctivitis sicca and uncover disease relevant therapeutic targets for this condition that affects up to 15% of the population over the age of 45 and has the potential to cause blindness.